This program is a competing continuation of NIH R01 EB002638 (formerly NIH R01 HL63953) "Improving the Diagnostic Potential of Optical Coherence Tomography for Vulnerable Plaque Assessment". The long- term objective of this work is to develop a new method of high resolution intravascular imaging to overcome current limitations in cardiac diagnostics, principally the identification of coronary plaques likely to lead to acute coronary syndromes (i.e. myocardial infarction or unstable angina). Most acute coronary syndromes (ACS) result from the rupture of small rather than large plaques in the coronary arteries. These vulnerable plaques are most typically thin cap fibroatheromas (TCFA) that contain a relatively large amount of complex necrotic core with a high concentration of lipid and hemorrhage, and an overlying thin collagen-depleted, intimal cap. When these plaques rupture, they release thrombogenic material into the blood, a clot forms, and the vessel frequently occludes. These small plaques are beyond the detection limit of any currently available imaging modalities. Optical coherence tomography (OCT), a new method of high resolution imaging, has demonstrated great potential for the assessment of unstable plaques. Preliminary data, generated in part through NIH RO1 HL55686 and R01 HL63953/ EB002638, has strongly suggested a feasibility of OCT for vulnerable plaque assessment. The 10 urn resolution allowed unprecedented definition of microstructure within arteries. As OCT is now being introduced for in vivo human imaging, allowing the identification of some TCFA, an important concern arises. Most ACS result from TCFA, but most TCFA do not lead to ACS. While OCT can identify plaques with intimal caps less than 70 urn, a substantial advance over other imaging modalities, a need exists for OCT to further risk stratify these plaques beyond the identification of TCFA, which is the current state of the art. If progress inthe field is to continue in the 21 st century, one must focus on high-risk patients with lesions that are vulnerable to thrombosis together with the triggering mechanisms that cause plaques to rupture at a precise location and time. The hypothesis of this proposal is that OCT technology can be advanced through the development of adjuvant technologies to improve risk stratification of thin cap atheromas, identifying those which lead to acute coronary syndromes. The hypothesis will be tested with advancements of the technology, assessment of in vitro human coronary arteries, imaging of in vitro RBC injected (hemorrhagic) atherosclerotic rabbit plaque (the current large animal model producing plaques most closely resembling human TCFA), in vivo imaging of rabbt atherosclerotic plaque, and monitoring in vivo changes induced with therapeutics. In addition, we will in parallel attempt to further improve the rabbit hemorrhagic plaque model by inducing angiogenesis, the factor which may ultimately be the trigger of many plaque ruptures.